Fentanyl is the common name for N-Phenyl-N-[1-(2phenylethyl)-4-piperidinyl]propanamide, a well-known powerful analgesic in the narcotic range and a known tranquilizer in veterinary practice. It is typically provided commercially in the form of the citrate salt also known as N-(phenethyl-4-piperdyl)propionanilide citrate.
An early process for the manufacture of fentanyl is found in U.S. Pat. No. 3,164,600 to Janssen. Following this early disclosure, precipitation and re-crystallization typically purified the product. Multiple precipitations were typically required to provide adequate purity for pharmaceutical use. In addition to yield loss in such processes, this practice greatly increases the complexity and cost of the product. Furthermore, precipitation processes can be lengthy requiring extended filtration time due to the particle size that is eventually produced.
One example of an attempt to improve the precipitation and crystallization process for pharmaceuticals such as fentanyl is disclosed in U.S. Pat. No. 6,596,206 to Lee. In this method a device for generating pharmaceutical agent particles using focused acoustic energy is disclosed. A solution of the pharmaceutical is provided in a suitable solvent into which is introduced a miscible “antisolvent” that upon admixture with the solution droplet causes the pharmaceutical agent in the droplet to precipitate. The focused acoustic energy causes a small droplet of the solution to be injected into antisolvent whereupon the pharmaceutical precipitates providing a small crystalline product. A device for accomplishing this method is also disclosed. Such method and device, while providing an improvement to the precipitation method still involves solvents, antisolvents and specialized equipment, all of which maintains the above noted disadvantages of the precipitation method for separating and purifying the pharmaceutical.
Other means to achieve separation or purification of pharmaceuticals includes adsorption processes such as the use of carbon. Another is the use of adsorption through ion exchange. Although this was done with alkaloids such as codeine and morphine, it has the limitation of requiring a low feed concentration. This is due to the need for the use of high pH flushes that can cause precipitation. Any precipitation can potentially compromise the entire purification process. Another disadvantage to this process is that significant salt is required so that another step of either dialysis or reverse osmosis is required for ion-removal.
Yet another way to achieve adsorption is through polar interaction or normal phase adsorption. Although this method is successful, it requires the extensive use of organic solvents. Moreover, although the alkaloids can be separated from each other, more evaporation is required.
Any use of analytical chromatography on narcotics such as fentanyl would guide an individual of ordinary skill in the art away from using preparative chromatography for an industrial scale process. Unlike preparative chromatography, analytical chromatography generally requires complete separation of each peak. Unlike preparative chromatography, complete separation of each peak is measured by ultraviolet (UV) absorbency. This is achieved by loading an infinitely small mass of the feed onto the column, and using a small particle size diameter (often less than 5 micrometers (196.85 microinches) in the stationary phase. The small particle size generates much higher pressures than those found in preparative chromatography. These higher pressures mandate the use of very large, strong and expensive chromatography equipment, which would negate the commercial viability for this analytical process. The equipment would also be very large in consideration that an infinitely small mass of feed is loaded in each run. In preparative chromatography, the objective is to recover the desired feed component with the required purity. The desired component can be recovered with impurities, so long as the impurities are within specification limits. The particle size of the stationary phase is small enough to achieve the separation, but is often greater than 10 microns (393.70 microinches). This limits the pressure drop generated. Also, in preparative chromatography, the maximum amount of feed is loaded with the constraint of attaining the desired product quality. This allows the product to leave the column with a maximum concentration, which then minimizes the size of the downstream equipment, especially any evaporating or concentrating units.
Various patents refer to preparative chromatography for the purpose of purifying or separating various non-ionic chemicals. Early patents in this field are U.S. Pat. No. 4,396,598 to Lin (X-ray contrast agents) and U.S. Pat. No. 5,204,005 to Doran, et al. In the '005 patent the process involves packing a chromatographic column with a chromatographic packing material, passing through the column a solution containing a water-soluble, nonionic contrast media compound and nonionic compounds as impurities at a loading ratio between approximately 10 to 1 to 1.5 to 1 weight packing material/total weight nonionic compounds. The column is then eluted to produce an eluate containing the nonionic contrast media compound.
Numerous publications followed the above '005 patent indicating various chromatographic systems, including flash, HPLC and preparative chromatography for separating various agents but not indicating conditions, clearly not teaching any industrial process. Such publications include Published Appln. US 2003/0087306, employing various chromatographic processes for separation of multimeric agents that modulate receptors, U.S. Pat. Nos. 6,395,752 and 6,127,385 indicating isomerization of L-threo-methylphenidate, U.S. Pat. No. 4,909,941 isolating recombinant deoxyribonucleic proteins, U.S. Pat. No. 6,261,537 relating to recovery of diagnostic/therapeutic agents having microbubbles coupled to one or more vectors, U.S. Pat. No. 6,331,289 relating to targeted diagnostic/therapeutic agents having more than one different vector and Published Appln. U.S. 2002/010227 relating to diagnostic therapeutic agents.
A reference to preparative, reverse phase chromatography including a loading ratio is U.S. Pat. No. 4,317,903 disclosing the purification of lincomycin hydrochloride indicating a loading weight ratio of 18 to 1, of bonded phase silica gel to starting material. A combination of chromatographic separation followed by nanofiltration with final discoloration by ion exchange resins is described in U.S. Pat. No. 5,811,581. The material being separated in the '581 patent is described as non-ionic, water-soluble, tri- and hexa-iodinated opacifying agents useful as contrast agents in X-ray imaging. The chromatographic process is operated with a weight ratio of stationary phase to raw product loaded in the range of 20:1 to lower than 0.5:1.
As can be seen by the above review of the prior art, numerous organic materials have been separated or purified by means of the chromatographic process. However, in most instances the conditions under which the chromatographic separation was carried out was not indicated. Also, the materials separated by means of the chromatographic processes are greatly dissimilar to the present objects of this invention, i.e. the industrial scale separation and purification of fentanyl. While there are numerous references to analytical chromatographic applications for fentanyl, there is no suggestion that an industrial process could be employed under any conditions.
The current process for the purification of fentanyl utilizes two crystallizations of the hydrochloride salt and one alkaloid precipitation to attain the desired purity. While the purity requirements are attained, the recovery is low as about half of the fentanyl is lost to the mother liquor streams generated due to the solubility of the hydrochloride salt. Recycling the fentanyl in these streams is difficult due to the elevated level of impurities. There is a need for a more efficient and direct method to isolate highly pure fentanyl.
The present invention is directed to overcoming one or more of the problems set forth above. These deficiencies and shortcomings include, but are not limited to, alkaloid yield loss, tedious manual solid handling operations such as the loading and unloading of centrifuges or filters, reliance on protective equipment by the operator, extensive processing steps and potential multiple precipitation in order to achieve the requisite purity requirements.